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Arquivos Brasileiros de Cardiologia - Volume 84, Nº 2, Fevereiro 2005
Case Report
Acute Renal Failure After Intravenous Use
of Immunoglobulin to Treat Myocarditis
Vitor Pordeus, Andréa Tostes, Cláudio Tinoco Mesquita, Charles Mady, Evandro Tinoco Mesquita
Rio de Janeiro, RJ / São Paulo, SP - Brazil
Hospital Pró-Cardíaco, Rio de Janeiro and Instituto do Coração of the Hospital das Clínicas of the FMUSP
Mailing address: Rua Figueiredo de Magalhães, 741/206 Cep 22031010 - Rio de Janeiro - RJ
E-mail: vitorpordeus@yahoo.com.br Received for publication: 06/14/2003 Accepted for publication: 05/26/2004 English version by Stela Maris Costalonga
The patient is a 60-year-old female with functional class III/ IV (NYHA) heart failure of an immunomediated etiology (autoim-mune myocarditis). After unsuccessful therapeutic attempts, intravenous immunoglobulin was used, leading to deterioration in renal function, a rare complication of that therapy. After hemodialysis, the patient’s renal function was restored, and the chronic heart failure improved to functional class I.
Myocardites constitute a group of diseases characterized by immuno-inflammatory aggression against the myocardium. The anatomicopathological substrate of this aggression has been clas-sically described as a cellular infiltration of lymphocytes, macro-phages, and other leukocytes, with destruction of cardiomyocytes, myocytolysis (Dallas criteria)1. In past years, advances in
unders-tanding of the complex pathophysiology of the disease and low sensitivity of the histopathological criteria have forced us to widen the model of aggression to beyond the immune response of the classical cellular type (Th1). Currently, we believe that an immu-nomediated aggression against the myocardium occurs, even when the infiltration of immunologic cells is absent. The characterization of pathogenic autoantibodies specific for more than a dozen au-toantigens has led us to a new model2. The etiology of those
diseases is still obscure. Activation of the immunologic system is known to occur, resulting in different forms of myocardial injury. The pathogenic stimuli that lead to the development of that car-diospecific aggression are yet to be elucidated.
The current major hypothesis is based on the model of viral infection as the promoter of the immune reaction directed against the heart. Different types of viruses, such as coxsackievirus, vovirus, adenovirus, cytomegalovirus, Epstein-Barr virus, and par-vovirus B19, have often been implicated. However, most clinical studies have shown great variability and low positivity in evidencing the viruses 1. Other clinical phenomena, such as skin diseases
(eg, psoriasis and vitiligo), systemic autoimmune diseases, and even intestinal diseases, such as celiac disease, have been signi-ficantly associated with myocardites, suggesting, therefore, a wide and complex pathophysiological model3.
The clinical findings of myocardites are highly varied. Their symptoms may range from fever and malaise to cardiac symptoms, such as palpitation, dyspnea, and chest pain. The physical exa-mination, and laboratory and radiological findings are not specific, making the diagnosis difficult, which requires an elevated clinical suspicion.
The most accurate noninvasive diagnostic method is indium-111 antimyosin myocardial scintigraphy4. This technique is not
available in our country. However, another technique of nuclear medicine that uses gallium 67, a marker of inflammation, has been used despite its lower sensitivity and specificity.
The endomyocardial biopsy, using Dallas histopathologic cri-teria, has been the standard diagnostic method, despite its low sensitivity. That technique has been boosted by the use of new in situ markers of immune activation, such as MHC class II (HLA-DR) and markers of lymphocytic populations, which increase the accuracy of that invasive diagnostic strategy.
Different groups have characterized pathogenic autoantibodies in that disease. Dozens of autoantigens have been implicated in myocardites, as well as in idiopathic dilated cardiomyopathy. Ho-wever, the serological tests have partially satisfactory results, using techniques such as enzyme (ELISA) and radioactive (RIA) immu-noassays2. Some authors2 have reported a 96% positivity in
pa-tients with myocarditis through biofunctional assays in a culture of murine cardiomyocytes, initiating a new field for the diagnosis of myocarditis: the measurement of specific autoantibodies.
Intravenous immunoglobulin has been used in cardiovascular diseases for a relatively short period, although its immunoregulatory function has been known for more than 2 decades. Different reports about its use in cardiology exist, mainly in peripartum cardiomyo-pathy, and, as recently reported, in chronic heart failure5.
Case Report
The patient is a 60-year-old female of mixed heritage, from the state of Rio de Janeiro, who reported dyspnea for 2 years, and, in the last 6 months, 3 episodes of acute pulmonary edema, despite being treated with an angiotensin-converting enzyme inhi-bitor (ACEI), a beta-blocker, and furosemide for heart failure.
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Arquivos Brasileiros de Cardiologia - Volume 84, Nº 2, Fevereiro 2005
Acute Renal Failure After Intravenous Use of Immunoglobulin to Treat Myocarditis
The echocardiogram showed left ventricular dilation with an ejection fraction of 25%. The patient underwent gallium-67 myo-cardial scintigraphy, which showed an image pattern of myomyo-cardial inflammation. An endomyocardial biopsy was performed, and its result was compatible with active lymphocytic myocarditis of mo-derate degree (Dallas criteria). The patient’s laboratory alterations were creatinine level of 2.2 mg/dL and hemoglobin of 12 g/dL.
Despite the optimized treatment with furosemide, carvedilol, spironolactone, and digoxin, the patient remained in NYHA func-tional class III/IV. Corticoid therapy and azathioprine were initiated, although the patient was using allopurinol for treating her previous hyperuricemia (uric acid = 11g%). The patient developed pancy-topenic hematopoietic hypoplasia, and azathioprine was suspen-ded. She remained symptomatic in functional class IV, with an identical clinico-functional pattern. We decided to use intravenous immunoglobulin at high doses, and the patient evolved with anuria and acute renal failure, when hemodialysis sessions were indicated for 2 weeks. At the end of that period, her renal function returned, and her urea and creatinine values returned to baseline. The patient’s clinical condition progressively improved, with stabilization of her cardiological findings and functional class I/II. So far, she has had no clinical problems.
Discussion
The use of intravenous immunoglobulin to treat primary and secondary deficiencies in antibodies began 25 years ago. Later it was used for the first time for an autoimmune disease, idiopathic thrombocytopenic purpura. Since then, this type of therapy has been used in different immunoinflammatory disorders, such as systemic lupus erythematosus, juvenile rheumatoid arthritis, and Guillain-Barré6. The mechanisms of action and the side effects
have not yet been totally elucidated, and the real efficacy in con-trolled clinical trials is yet to be revealed.
In 1994, Caforio et al2, in an open study, reported an
improve-ment in cardiac function and survival in children with myocarditis with the use of intravenous immunoglobulin.
The physiological role of the antibodies and of the immune system itself in our body requires clarification, so that the real action of intravenous gamma globulins can be understood. Howe-ver, among the effects reported in vivo and in vitro, overall regulation of the immune response is observed: the complement cascade has smaller parameters of activation. There is still the reduction in the serum concentrations of inflammatory markers, such as IL-6 and TNF-α, which are produced by some cell types, such as
macrophages and T lymphocytes CD4. Lower degrees of activation, differentiation, and clonal expansion of lymphocytic populations, both B and T, are seen4.
Several populations of immune cells, such as macrophages, B lymphocytes, and mast cells, have receptors for the constant fraction of immunoglobulins linked to inhibitory domains of the immune response, ie, transmembrane proteins, whose activation triggers the action of intracytoplasmic proteins that inhibit factors of activation, such as NFêB. Those activation factors cause the synthesis of inflammatory mediators, from specific genome
pro-grams, suggesting that those populations could be hindered by the constant fractions of intravenous immunoglobulins.
The effects of the intravenous immunoglobulins on the complex idiotypic network of antibodies should be considered, because they can recognize the specific regions of other antibodies, constituting a complex network of connectivity and interregulation among the immunoglobulins. Such phenomenon has also been observed in the receptors of T-TCR cells, however, it has been less characterized8.
Solid evidence has indicated that those physiologically auto-reactive antibodies can act by regulating each other, which may occur in immunomediated diseases, such as autoimmune myocarditis, un-controlled expansions of sectors of that system in constant equili-brium, oligoclonal expansions. Oligoclonal expansions of lymphocytes occur every time a certain antigen should be eliminated, and they lead to a reorganization of the network, which leads to the eli-mination of those activated clones. In such situations, in which the myocardium is injured, an imbalance of the system occurs, resulting in maintenance of oligoclonality. Intravenous immunoglobulins are believed to reestablish the equilibrium of the idiotypic network, hindering oligoclonal expansions, and stopping the aggression against the target organ.
The effects of gamma globulin on the process of cardiac re-modeling should also be highlighted; patients treated with it have smaller indices of chamber dilation, and greater and more stable left ventricular ejection fraction9.
Side reactions to intravenous immunoglobulin have been re-ported in less than 5% of patients. Of the side effects, aseptic meningoencephalitis, peripheral neuritis, cutaneous rash, and cephalea stand out1.
Acute renal failure is a rare complication with approximately 150 cases reported in the literature10 and has been associated
with diabetes, preexisting renal disease, advanced age, and ad-ministration of intravenous immunoglobulin in saccharose-based solutions. Adverse thrombotic events have also been reported, such as acute myocardial infarction and stroke. Our patient was advanced in age and had previous renal dysfunction. The patho-physiology of that adverse effect should still be more thoroughly investigated. The immunocomplexes are believed to build up in the glomerular lumen, leading to acute glomerulonephritis, which is self-limited and resolves spontaneously in a few weeks.
Our patient also had pancytopenia, which may be explained by the characteristic of the active metabolite of azathioprine (6-mercaptopurin) to be cleared, among other pathways, by xanthine oxidase, the most important enzyme inhibited by allopurinol, which potentiates its toxic effects due to the decreased clearance.
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Arquivos Brasileiros de Cardiologia - Volume 84, Nº 2, Fevereiro 2005
Acute Renal Failure After Intravenous Use of Immunoglobulin to Treat Myocarditison
1. Feldman AM, McNamara D. Myocarditis. N Eng J Med 2000; 343: 1388-98. 2. Caforio AL, Mahon NJ, Tona F, McKenna WJ. Circulating cardiac autoantibodies
in dilated cardiomyopathy an myocarditis: pathogenetic and clinical significance. The Eur J Heart Failure 2002; 4:411-417.
3. Frustaci A, Cuoco L, Chimenti C, et al. Celiac disease associated with autoimmune myocarditis. Circulation 2002; 105: 2611-2618.
4. Narula J, Khaw BA, Dec Gw, et al. Diagnostic accuracy of antimyosin scintigraphy in suspected myocarditis. J Nucl Cardiol 1996;3:371-81.
5. Aukrust P, Yndestad A, Damas JK, Gullestad L. Inflamation and chronic heart failure – potential therapeutic role for intravenous immunoglobulin. Autoimmunity Reviews 2003, in press.
6. Kazatchikine MD, Kaveri SV. Immunomodulation of autoimmune and inflamatory diseases with intravenous immune globulin. N Engl J Med 2001; 345: 747.
References
7. Drucker NA, Colan SD, Lewis AB, et al. Gamma-globulin treatment of acute myo-carditis in the pediatric population. Circulation 1994;89:252-7.
8. Jerne N. The generative grammar of the immune system.[on line] Aula Nobel apre-sentada em 10 de dezembro de 1984 no Instituto Karolinska, Estocolmo, Suécia. Disponível na World Wide Web, acessado em 10 de junho de 2003 [http:// www.nobel.se/medicine/laureates/1984/jerne-lecture.html]
9. Tedeschi A, Airaghi L, Gianini S, Ciceri L, Massari FM. High-dose intravenous im-munoglobulin in the treatment of acute myocarditis. A case report and a review of the literature. J Internal Med 2002; 251:169-173.
